High-Dose Cisplatin and Dacarbazine in the Iteatment of Metastatic Melanoma Selina M. Luger, John M. Kirkwood, Marc S. Ernstoff, Daniel R. Vlock*
Results Patient characteristics are summarized in Table 1. Patients had a median of two sites of metastatic involvement
Patients and Methods Twenty-eight patients with metastatic melanoma were entered in the study. All patients had measurable or assessable metastases, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a life expectancy of at least 3 months. Patients who had received prior therapy with DTIC or CDDP were ineligible to participate. Patients with documented central nervous system (CNS) metastases who had disease progression following treatment with radiation therapy were eligible for treatment. Patients with a creatinine clearance ^60 mg/minute, white blood cell count less than 3500/mm3, and platelet count less than 100000/mm3 were excluded. Prior to entering the study, all patients signed an informed consent. The protocol was approved by the 1934
in the following areas: soft tissue, lung, liver, brain, small bowel, spleen, and adrenal gland. Eleven patients (39%) had received prior therapy; of these patients, eight had received immunotherapy; six, radiotherapy; and two, chemotherapy. The ECOG performance status was 0 to 2. Of the 74 cycles of chemotherapy administered, 17 (22%) were modified because of toxicity (Table 2). Nausea and/or vomiting was noted in 50% of treatment courses and was more pronounced the week following administration of chemotherapy, hi the majority of cases, this was well controlled with antiemetics. Grade 3 to 4 leukopenia and thrombocytopenia were documented in 51% and 44% of the courses,respectively.While 40% of the cycles were associated with mild elevations of serum creatinine levels, only 2% had documented grade 3 or 4 toxicity. All of these cycles were associated with azotemia, which responded to hydration. Creatinine levels returned to baseline within 1 month in all but three patients. One patientls creatinine level rose to 8.7 mg/dL immediately
Received August 1, 1990; revised September 27, 1990; accepted October 1, 1990. Division of Medical Oncology, Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pa. *Correspondence to: Daniel R. Vlock, MD, Hematology/Oncology, VA Medical Center, University Dr C, Pittsburgh, PA 15240.
Table 1. Patient characteristics and response rate Characteristic
No. of patients (%)
Total
28
(100)
Response Partial*
Complete*
Total, %
7
1
29
Age range: 27-74 y\ Sex Female Male
12 (43) 16 (57)
6 1
0 1
50 12
Performance status 0 1 2
11 (40) 11 (40) 6 (20)
2 4 1
1 0 0
27 36 17
Prior treatment Yes No
11 (39) 17 (61)
4 3
1 0
45 18
Metastases Soft tissue Lung liver CNS Other viscera
18 16 13 5 8
4 3 3 1 1
0 1 0 0 0
22 25 23 20 12
(65) (57) (46) (18) (28)
•Values = No. of patients. fMean = 49 y; median = 47 y.
Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of Glasgow on June 28, 2015
The current standard of therapy for metastatic melanoma consists of dacarbazine (DTIC) alone or in combination with other agents (7); this therapy results in response rates in the range of 10% to 20%. Cisplatin (CDDP) has been used as a single agent in the treatment of metastatic melanoma and elicits response rates of 15% to 29% (2-5). There have been a number of studies evaluating combination DTIC/CDDP therapy (6-9). Del Prete et al (10), using higher combined doses of DTIC/CDDP, demonstrated a response rate of 55% in 20 patients. The most significant toxic effects reported were renal and neurologic, with only mild hematologic toxicity. This observation suggests that dose intensification, which has been viewed as a means of improving cytotoxic therapy, could improve response rates in metastatic melanoma. We report our experience with the highest dosages of CDDP/DTIC yet studied in the treatment of metastatic melanoma.
Institutional Review Board of Presbyterian University Hospital. Chemotherapy consisted of CDDP (40 mg/m2 per day) for 5 days and DTIC (500 mg/m2 per day) on days 1 and 2, on a cycle of every 28 days. Initially, CDDP was administered over 6 hours. After an episode of acute renal failure was observed in one of the first six patients, however, CDDP administration was subsequently changed to continuous administration over 24 hours, and DTIC was administered as a 20-minute bolus on days 1 and 2. Antiemetics were administered prior to, during, and, to prevent delayed nausea, for 5 days following chemotherapy. Therapy was continued for a minimum of three cycles unless progressive disease or patient intolerance to the regimen precluded further therapy. Dosages were modified for grade 3 or grade 4 myelosuppression or nephrotoxicity. Patients were evaluated for response after completion of three cycles of treatment. Toxicity was graded according to ECOG toxicity criteria (77); hypokalemia, however, was graded as follows: grade 1: 3.2 to 3.4 mEq/L; grade 2:2.9 to 3.1 mEq/L; grade 3:2.5 to 2.8 mEq/L; grade 4
Results Patient characteristics are summarized in Table 1. Patients had a median of two sites of metastatic involvement
Patients and Methods Twenty-eight patients with metastatic melanoma were entered in the study. All patients had measurable or assessable metastases, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a life expectancy of at least 3 months. Patients who had received prior therapy with DTIC or CDDP were ineligible to participate. Patients with documented central nervous system (CNS) metastases who had disease progression following treatment with radiation therapy were eligible for treatment. Patients with a creatinine clearance ^60 mg/minute, white blood cell count less than 3500/mm3, and platelet count less than 100000/mm3 were excluded. Prior to entering the study, all patients signed an informed consent. The protocol was approved by the 1934
in the following areas: soft tissue, lung, liver, brain, small bowel, spleen, and adrenal gland. Eleven patients (39%) had received prior therapy; of these patients, eight had received immunotherapy; six, radiotherapy; and two, chemotherapy. The ECOG performance status was 0 to 2. Of the 74 cycles of chemotherapy administered, 17 (22%) were modified because of toxicity (Table 2). Nausea and/or vomiting was noted in 50% of treatment courses and was more pronounced the week following administration of chemotherapy, hi the majority of cases, this was well controlled with antiemetics. Grade 3 to 4 leukopenia and thrombocytopenia were documented in 51% and 44% of the courses,respectively.While 40% of the cycles were associated with mild elevations of serum creatinine levels, only 2% had documented grade 3 or 4 toxicity. All of these cycles were associated with azotemia, which responded to hydration. Creatinine levels returned to baseline within 1 month in all but three patients. One patientls creatinine level rose to 8.7 mg/dL immediately
Received August 1, 1990; revised September 27, 1990; accepted October 1, 1990. Division of Medical Oncology, Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pa. *Correspondence to: Daniel R. Vlock, MD, Hematology/Oncology, VA Medical Center, University Dr C, Pittsburgh, PA 15240.
Table 1. Patient characteristics and response rate Characteristic
No. of patients (%)
Total
28
(100)
Response Partial*
Complete*
Total, %
7
1
29
Age range: 27-74 y\ Sex Female Male
12 (43) 16 (57)
6 1
0 1
50 12
Performance status 0 1 2
11 (40) 11 (40) 6 (20)
2 4 1
1 0 0
27 36 17
Prior treatment Yes No
11 (39) 17 (61)
4 3
1 0
45 18
Metastases Soft tissue Lung liver CNS Other viscera
18 16 13 5 8
4 3 3 1 1
0 1 0 0 0
22 25 23 20 12
(65) (57) (46) (18) (28)
•Values = No. of patients. fMean = 49 y; median = 47 y.
Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of Glasgow on June 28, 2015
The current standard of therapy for metastatic melanoma consists of dacarbazine (DTIC) alone or in combination with other agents (7); this therapy results in response rates in the range of 10% to 20%. Cisplatin (CDDP) has been used as a single agent in the treatment of metastatic melanoma and elicits response rates of 15% to 29% (2-5). There have been a number of studies evaluating combination DTIC/CDDP therapy (6-9). Del Prete et al (10), using higher combined doses of DTIC/CDDP, demonstrated a response rate of 55% in 20 patients. The most significant toxic effects reported were renal and neurologic, with only mild hematologic toxicity. This observation suggests that dose intensification, which has been viewed as a means of improving cytotoxic therapy, could improve response rates in metastatic melanoma. We report our experience with the highest dosages of CDDP/DTIC yet studied in the treatment of metastatic melanoma.
Institutional Review Board of Presbyterian University Hospital. Chemotherapy consisted of CDDP (40 mg/m2 per day) for 5 days and DTIC (500 mg/m2 per day) on days 1 and 2, on a cycle of every 28 days. Initially, CDDP was administered over 6 hours. After an episode of acute renal failure was observed in one of the first six patients, however, CDDP administration was subsequently changed to continuous administration over 24 hours, and DTIC was administered as a 20-minute bolus on days 1 and 2. Antiemetics were administered prior to, during, and, to prevent delayed nausea, for 5 days following chemotherapy. Therapy was continued for a minimum of three cycles unless progressive disease or patient intolerance to the regimen precluded further therapy. Dosages were modified for grade 3 or grade 4 myelosuppression or nephrotoxicity. Patients were evaluated for response after completion of three cycles of treatment. Toxicity was graded according to ECOG toxicity criteria (77); hypokalemia, however, was graded as follows: grade 1: 3.2 to 3.4 mEq/L; grade 2:2.9 to 3.1 mEq/L; grade 3:2.5 to 2.8 mEq/L; grade 4
